This invention relates generally to the topical and transdermal administration of pharmacologically active agents, and more particularly relates to methods, drug delivery systems and pharmaceutical compositions for transdermal administration of phenylpropanolamine.
The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniencesxe2x80x94e.g., gastrointestinal irritation and the likexe2x80x94are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low without the use of some means to enhance the permeability of the skin.
In order to increase the rate at which a drug penetrates through the skin, then, various approaches have been followed, each of which involves the use of either a chemical penetration enhancer or a physical penetration enhancer. Physical enhancement of skin permeation includes, for example, electrophoretic techniques such as iontophoresis. The use of ultrasound (or xe2x80x9cphonophoresisxe2x80x9d) as a physical penetration enhancer has also been researched. Chemical enhancers are compounds that are administered along with the drug (or in some cases the skin may be pretreated with a chemical enhancer) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin. Ideally, such chemical penetration enhancers (or xe2x80x9cpermeation enhancers,xe2x80x9d as the compounds are referred to herein) are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum.
Nevertheless, the number of drugs that can be safely and effectively administered through the skin, without concomitant problems such as irritation and sensitization, remains limited.
The present invention is directed to the transdermal administration of 2-amino-1-phenyl-1-propanol, or xe2x80x9cphenylpropanolamine.xe2x80x9d The drug is described, for example, by Kanfer et al., in Analytical Profiles of Drug Substances, vol. 12, K. Florey, Ed. (New York: Academic Press, 1983). Phenylpropanolamine is a sympathomimetic agent that has been used as an anorectic agent, a decongestant, an anxiolytic agent, and as a drug for decreasing fatigue and confusion. See, for example, U.S. Pat. No. 5,019,594 to Wurtman et al., U.S. Pat. No. 5,260,073 to Phipps, and U.S. Pat. No. 5,096,712 to Wurtman.
Phenylpropanolamine has the molecular structure (I) 
and, as may be seen contains two chiral centers. Thus, phenylpropanolamine exists as four different isomers, as follows: 
Isomers (Ia) through (Id) are generally referred to as (+)-norephedrine, (xe2x88x92)-norephedrine, (+)-norpseudoephedrine, and (xe2x88x92)-norpseudoephedrine, respectively. Generally, isomers (Ib) and (Ic), i.e., (xe2x88x92)-norephedrine and (+)-norpseudoephedrine, are recognized as the more active isomers for most physiological uses. The typical formulation, however, is a racemic mixture of (+)-norephedrine and (xe2x88x92)-norephedrine. This mixture, generally referred to as (xc2x1)-phenylpropanolamine (or simply xe2x80x9cphenylpropanolaminexe2x80x9d), is commercially available for use as an anorectic agent at a dose of about 50-75 mg/day, and as a nasal decongestant at a dose of about 75-150 mg/day.
Currently, phenylpropanolamine is administered orally, in tablets, capsules or syrups. The present invention, however, is directed to the transdermal administration of phenylpropanolamine. There are a number of other advantages to administering phenylpropanolamine transdermally: continuous delivery provides for sustained blood levels of the otherwise short-lived drug (the half-life of phenylpropanolamine is on the order of 3.8 to 4.3 hoursxe2x80x94see Scherzinger et al. (1990) J. Clin. Pharmacol. 30(4):372-377); there is no first-pass effect; side effects typically associated with oral administration may be substantially avoided; continuous delivery provides for sustained blood levels; the transdermal patch is easily removable if any side effects do occur; and the likelihood of both patient acceptance and patient compliance is significantly improved.
Transdermal administration of phenylpropanolamine has been proposed. In U.S. Pat. No. 4,818,541, transdermal systems are disclosed for delivering phenylpropanolamine to the skin. In the aforementioned patent, however, it is noted that the skin flux of (xc2x1)-phenylpropanolamine (i.e., a mixture of (xe2x88x92)-norephedrine and (+)-norephedrine) is only 16 xcexcg/cm2/hr, although the skin flux of individual enantiomers was found to be higher. Furthermore, the method of the ""541 patent requires neutralization of phenylpropanolamine hydrochloride (i.e., conversion to the free base), the commercially available form of the drug, before incorporation into a transdermal drug delivery system.
Accordingly, there is a need in the art for a way to transdermally administer racemic phenylpropanolamine without being limited by the racemate""s low skin flux, and without having to convert phenylpropanolamine hydrochloride to the base form of the drug prior to patch manufacture. The terms xe2x80x9cracemicxe2x80x9d or xe2x80x9cracematexe2x80x9d as used herein refer to a mixture of any two or more of the four isomers of phenylpropanolamine, but typically refer to a mixture of (xe2x88x92)-norephedrine and (+)-norephedrine.
Various compounds for enhancing the permeability of skin are known in the art and described in the pertinent texts and literature. Compounds that have been used to enhance skin permeability include: the sulfoxides dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol(copyright)) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone(copyright) from Nelson Research and Development Co., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanol amine, diethanol amine and triethanolamine; terpenes; alkanones, and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid. Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995) provides an excellent overview of the field and further background information on a number of chemical and physical enhancers.
Although many chemical permeation enhancers are known, there is an ongoing need for enhancers that are highly effective in increasing the rate at which a drug permeates the skin, do not result in skin damage, irritation, sensitization, or the like, and also allows neutralization of phenylpropanolamine hydrochloride during, rather than prior to, patch manufacture. It has now been discovered that hydroxide-releasing agents are highly effective permeation enhancers, even when used without co-enhancers, providing all of the aforementioned advantages relative to known permeation enhancers. Furthermore, in contrast to conventional enhancers, transdermal administration of drugs with hydroxide-releasing agents as permeation enhancers, employed at the appropriate levels, does not result in systemic toxicity.
It is thus a primary object of the invention to address the above-described need in the art by providing drug delivery systems, pharmaceutical formulations and methods for the transdermal administration of racemic phenylpropanolamine in neutral, uncharged form.
It is another object of the invention to provide a method for treating conditions, disorders or diseases that are responsive to administration of phenylpropanolamine by transdermally administering racemic phenylpropanolamine to a patient in need of such therapy.
It is still another object of the invention to provide a method for administering racemic phenylpropanolamine transdermally at a flux that is therapeutically effective for use as anorectic agent, a decongestant, an anxiolytic agent, or to decrease fatigue or confusion.
It is yet another object of the invention to provide a transdermal drug delivery system for administration of racemic phenylpropanolamine such that a therapeutically effective skin flux is achieved.
It is a further object of the invention to provide a chemical composition containing racemic phenylpropanolamine, formulated for transdermal drug delivery.
It is still a further object of the invention to provide a method for manufacturing a transdermal drug delivery system wherein phenylpropanolamine hydrochloride is converted to phenylpropanolamine base during system manufacture.
It is yet a further object of the invention to provide a method for administering racemic phenylpropanolamine transdermally in combination with a basic permeation enhancer.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, then, a method is provided for treating an individual suffering from a condition, disease or disorder that is responsive to administration of phenylpropanolamine, by transdermally administering a therapeutically effective amount of racemic phenylpropanolamine. The method is premised on the discovery that racemic phenylpropanolamine may in fact be administered through the skin or mucosal tissue at a therapeutically effective rate to achieve desired systemic effects, when a permeation enhancer, particularly a basic permeation enhancer, is coadministered with the drug.
In another aspect of the invention, a pharmaceutical composition and a transdermal therapeutic system are provided for transdermal administration of racemic phenylpropanolamine. The pharmaceutical composition contains racemic phenylpropanolamine, and is formulated for transdermal drug delivery. The transdermal drug delivery system is a laminated composite comprising a backing layer, a drug reservoir, and a means for affixing the composite to the skin. The drug reservoir and the affixing means may be distinct, such that a separate contact adhesive layer is provided which serves as the basal surface of the device, or the drug reservoir may itself be comprised of an adhesive layer which is suitable for contacting and adhering to the skin. Such therapeutic systems are in the nature of xe2x80x9csolid matrixxe2x80x9d type transdermal patches. Alternative systems, containing the drug in a liquid, gel or foam reservoir, may, however, be used as well.
In another aspect of the invention, a method is provided for increasing the rate at which phenylpropanolamine permeates through the body surface of a patient. The method involves administering the drug to a predetermined area of the patient""s body surface in combination with a hydroxide-releasing agent in a predetermined amount effective to enhance the flux of the agent through the body surface without causing damage thereto. The predetermined amount of the hydroxide-releasing enhancer is preferably an amount effective to provide a pH at the body surface in the range of about 8.0 to 13, preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5, during drug administration. If a skin patch is used, this is the preferred pH at the interface between the basal surface of the patch (i.e., the skin-contacting or mucosa-contacting surface of the patch) and the body surface. The optimal amount (or concentration) of any one hydroxide-releasing agent will, however, depend on the specific hydroxide-releasing agent, i.e., on the strength or weakness of the base, its molecular weight, and other factors as will be appreciated by those of ordinary skill in the art of transdermal drug delivery. This optimal amount may be determined using routine experimentation to ensure that the pH at the body surface is within the aforementioned ranges, i.e., in the range of about 8.0 to 13, preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5. A conventional transdermal drug delivery device or xe2x80x9cpatchxe2x80x9d may be used to administer the active agent, in which case the drug and hydroxide-releasing agent are generally present in a drug reservoir or reservoirs. However, the drug and hydroxide-releasing agent may also be administered to the body surface using a liquid or semisolid formulation. Alternatively, or in addition, the body surface may be pretreated with the enhancer, e.g., treated with a dilute solution of the hydroxide-releasing agent prior to transdermal drug administration. Such a solution will generally be comprised of a protic solvent (e.g., water or alcohol) and have a pH in the range of about 8.0 to 13, preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5.
In a related aspect of the invention, a composition of matter is provided for delivering phenylpropanolamine through a body surface using a hydroxide-releasing agent as a permeation enhancer. Generally, the formulation comprises (a) a therapeutically effective amount of a drug, (b) a hydroxide-releasing agent in an amount effective to enhance the flux of the drug through the body surface without causing damage thereto, and (c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration. The composition may be in any form suitable for application to the body surface, and may comprise, for example, a cream, lotion, solution, gel, ointment, paste or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres. The composition may be directly applied to the body surface or may involve use of a drug delivery device. In either case, it is preferred although not essential that water be present in order for the hydroxide-releasing agent to generate hydroxide ions and thus enhance the flux of the active agent through the patient""s body surface. Thus, a formulation or drug reservoir may be aqueous, i.e., contain water, or may be nonaqueous and used in combination with an occlusive overlayer so that moisture evaporating from the body surface is maintained within the formulation or transdermal system during drug administration. In some cases, however, e.g., with an occlusive gel, a nonaqueous formulation may be used with or without an occlusive layer.
In another aspect of the invention, a drug delivery system is provided for the topical or transdermal administration of a drug using a hydroxide-releasing agent as a permeation enhancer. The system will generally comprise: at least one drug reservoir containing the drug and the hydroxide-releasing agent in an amount effective to enhance the flux of the drug through the body surface without causing damage thereto; a means for maintaining the system in drug and enhancer transmitting relationship to the body surface; and a backing layer that serves as the outer surface of the device during use. The backing layer may be occlusive or nonocclusive, although it is preferably occlusive. The drug reservoir may be comprised of a polymeric adhesive, which may serve as the basal surface of the system during use and thus function as the means for maintaining the system in drug and enhancer transmitting relationship to the body surface. The drug reservoir may also be comprised of a hydrogel, or it may be a sealed pouch within a xe2x80x9cpatchxe2x80x9d-type structure wherein the drug and hydroxide-releasing agent are present in the pouch as a liquid or semi-solid formulation.